Derivatives of thiophan-3-one-4-carboxylic-acid-esters and process for the manufacture of same



Patented Feb. 18, 194-7 DERIVATIVES OF THIOPHAN-3-ONE-4-CAR- BOXYLIC-AClD-ESTERS, AND PROCESS FOR THE MANUFACTURE OF SAME Paul Karrer, Zurich, Switzerland, assignor to Hoffmann-La Roche Inc.,- Nutley, N. J a corporation of New Jersey No Drawing. Application December 21, 1943, Serial No. 515,170. In Switzerland February 1 Thiophan-3-one-4-carboxylic-acid-esters, carrying in position 2 an aliphatic substituent (X) and corresponding to Formula I COOR | CH-CO wherein R represents a lower alkyl radical and X an aliphatic substituent are valuable starting materials for the manufacture of therapeutically employable preparations capable of exerting the pharmacological activity of biotin. The substituent X in position 2 may, for instancacon-- sist of the following radicals:

CH1 CH\ -CH2CH1COOC1H5, HzCHzCH=0OHs,

(CH2)4OCH3, (CH2)4CN It has been found that compounds of the said const1tution may be obtained by treating sulfidep-propionic-acid-(X-acetic-acid) -esters of For-' mula II OOOR Hz C 0 OR II CH2 HX 12 Claims. (Cl. 260-329) off in vacuo, the residue is taken up in little water and extracted with ether. After evaporation of the solvent, sulfide-B-propionic-acid-(u glutaricacid.) -ester of Formula III CH2 0 O 0 0 E;

( 3E, oaornomoooozm is obtained as a colorless liquid, distilling over at 150-153 C. under a pressure of 0.02 mm. Hg.

In order to transform this compound into the thiophanone derivative of Formula IV HCO H2 (EHCHflOHICOOCQHI 1.9 parts by weight of the former are added drop by drop to a suspension of 0.8 part by weight of amorphous-sodium ethylate in parts by volume of toluenewhile stirring. The reaction mixture is heated to C. for 9 hours while stirring is continued. The reaction product is then poured on ice, to which 1.5 parts by volume of glacial acetic acid were added, extracted with peroxidefree ether, and. the ether is driven off. The oil remaining behind distills over at 123 C. under a pressure, of 0.02 mm. Hg as a colorless liquid.

' The compound which showsan intensive red wherein R represents a lower alkyl group and X an aliphatic radical, with condensing agents, such as lower alkali alcoholate, alkali amide, and similar means. Hereby the formation of a ring takes place and compounds corresponding to Formula I are obtained.

The new compounds are to be used for the manufacture of therapeutics.

Example 1 The reaction materials are leftto stand for two hours in the freezing mixture, whereupon they are heated to 15 C. for half an hour, and, finally, to boiling for 30 minutes. The alcohol is driven violet coloring with iron chloride is the 2-(carbethoxy-ethyl) -thiophan-3-onecarboxyliceacidethyl-ester of Formula IV.

Example 2 7.5 parts by weight of ,B-mercapto-propionicf acid-ethyl-ester, dissolved in 5parts by volume of alcohol, are added drop by .drop to an ice-cold solution of 1.08 parts by Weight of "sodium in 18 parts by volume 'of absolute alcohol. Under an atmosphere of nitrogen, 11.8 parts by weight of u-bromo-omega-methoxy-capronic acid ethylester, dissolvedin 10 parts by volume of absolute alcohol, are added at '20C. The mixture is left to stand ford-5 hours in the freezing .mixture While shaking vigorously, then heated to 15. CL for one hour and, finally, for a short timeon a boillng water bath. The alcohol is driven off in vacuo, the residue taken up in little water, shaken out with peroxide-free ether, whereupon the solvent is evaporated and the residue is fractionated in high, vacuo. Sulfide-p-propionic-acid-a-(omegadistills over under a pressure of 0.025 mm. Hg at 142 C. as a. colorless oil.

'The cyclisation of the compound to the corre scribed in Example 1.

thus obtained distills over at 110-115 C. under a pressure-of 0.025 mm. Hg as a colorless oil showing an intensive red-violet coloring with iron chloride.

I claim:

1. 2-(carbethoxy-ethyl) -thiophan 3 one 4 carboxylic-acideethyl-ester having the formula:

' COOCzHs (1H on, tnomomoooczm S l 2. 2-(omega-methoxy butyl) thiophan 3 I one-4carboxylic acid-ethyl-ester having the formula:

oooolm 3. Process for the manufacture of 2-(carbethoxy-ethyl) -thiophan-3-one-4-carboxylic acid ethyl-ester, comprising treating sulfide-p-propionic-acid-(m-glutaric-acim-ester of. the formula coon V I on, coon v om 'cmomomooon wherein- R represents asaturatedlower alkyl radical, with an alkaline condensing agent'capable of promoting ring closure.

4. Process for the manufacture of 2- (carbethv oXy-ethyl)-thiophan-3-one-4-carboxylic acid ethyl-ester, comprising n treating sulfide-,S-propionic-acid- (u-glutaric-acid) -ethyl-ester of the I 'formula 7 0 o O'CzHs H1 00 00am on, CH.CH1GH2GOQC1HI with sodium ethylate.

'. Process for the manufacture of 2- ('omega methoxy-butyll-thiophan-3-one 4 carboxylicacid-ethyl-ester, comprising treating sulfide- 3- propionic-acid-a-(omega methoxy capronic acid) -ester of the formula COOR CH: CE:

000R /CH.(CH )4O CH:

3 f methoxy capronic acid) ethyl ester of Formula V C O O CzHu CH2 COOCzHg V CE: onmmhoom sponding thiophanonederivative is effected by the aid of amorphous sodium-ethylate dissolved in,

toluene in a manner analogous to the one de- The 2-(omega-methoxybutyl)-thiophan-3-one-4-carboxylicracid ethyl- I'ester of Formula VI wherein R represents a saturated lower alkyl' radical, with an alkaline condensing agent capable of promoting ring closure.

6. Process for the manufacture of 2- (omegamethoxy-butyl)-thiophan-3-one 4 carboxylicacid-ethyl-ester, comprising treating sulfide-,6- propionic-acid-a(omega s methoxy capronic acid) -ethyl-ester of the formula COOCzH'a CJH: COOCzHs .Hn H.(CHQ)4OCH5 I s with sodium ethylate.

7. Thi0phan-3-one-4-carboxylic-acid-esters' of the formula: 7

CH-CO (1H2 (IHX wherein R represents a lower alkyl radical and X is a substituted alkyl group selected from the group consisting of X is a substituted alkyl selected from the group consisting of --(CHz)4,OOHa, (OHZ)4ON with an alkaline condensing agent capable of promoting ring closure.

10. The method of claim 6 in which the con-' densing agent is a lower alkali alcoholate.

11. The method of claim 6 in which the condensing agent is sodium ethylata,

12. The method of claim 6 in which the condensing agent is an alkali amide.

, PAUL KARRER.

REFERENCES CITED The following references are of record in the file of this patent:

FOREIGN PATENTS Number Country Date 282,914 German Mar. 22,1915

OTHER REFERENCES 4 75J0urnal of Biochemistry, vol. 146 (1942), page 

